In medicinal chemistry and chemical biology, researchers are constantly expanding the chemical space to develop innovative approaches with therapeutic value. For example, peptides, which have been chemically modified to retain a bioactive conformation, have found wide application in the modulation of protein–protein interactions (PPIs). These so-called constrained or stabilized peptides can bind proteins selectively and with high affinity. Compared to all-natural peptides they often show increased plasma stability and cellular uptake, which renders them potentially useful for the inhibition of intracellular targets. To obtain PPI inhibitors, constrained peptides can be derived from the interfaces of PPIs by using the underlying peptide binding motifs as inspiration. The bioactive conformation of such natural peptide motifs can be stabilized through the implementation of constraints, e.g., via peptide backbone modification or macrocyclization. This thesis presents constrained peptides from structure-based approaches that inhibit PPIs of transcription factors. To enable the design of high-affinity peptides, established stabilization methodologies have been applied, refined, and complemented.
|Award date||30 Nov 2021|
|Publication status||Published - 30 Nov 2021|